Protein@PP-Zn nanocomplex assembled by coordination of zinc ions used for intracellular protein delivery

In recent years, intracellular delivery of protein drugs has attracted great attention, and polymer-based systems have been extensively exploited to develop efficient and safe carriers. However, efficient intracellular delivery of protein drugs remains a challenge because of the cell membrane barrier and endosome entrapment. Herein, we report a protein@PP-Zn nanocomplex, which consists of an imidazole-containing block polymer poly(ethylene glycol)-block-poly(β-amino ester) (PEG- b -PAE(Im), PP), zinc ions, and protein drugs, for efficient intracellular protein delivery. PEG- b -PAE(Im) could conjugate proteins via the bridging effect of zinc ions which simultaneously coordinate with imidazole groups on polymer and electron donor groups, such as imidazole and primary amine groups, on protein to improve the loading stability of proteins. Under a slightly acidic environment near cancer cells, the protonation of PAE(Im) backbone increases the positive charge density of the nanocomplex and promotes endocytosis. While under a more acidic environment in endosomes, further protonation of imidazole groups leads to the disintegration of the nanocomplex and the breakdown of endosomes because of the proton sponge effect. Finally, protein is released into the cytoplasm. With the assistance of the nanocomplex, proteins with different sizes and isoelectric points are effectively delivered into cells. This work provides a stable, efficient and universal strategy for intracellular protein delivery.